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Pancreatitis in childhood ALL
AAP. The variant rs62228256 [reference allele=C, minor allele=T (C>T)] on 20q13.2 showed the strongest associa- tion with AAP [odds ratio (OR), 3.75; 95% confidence interval (95% CI): 2.33 to 6.04; P=5.2 x 10-8). rs62228256 is located 274 kilobase pairs upstream of Nuclear factor of activated T cells (NFATC2) and has been documented to be an expressive quantitative trait locus for this gene in pancreatic tissue (Online Supplementary Figure S5).
The 30 SNPs most associated with AAP, with P-values of 5 x 10-5 or lower, included rs13228878 (A>G; OR, 0.61; 95% CI: 0.5 to 0.76; P=7.1 x 10-6) and rs10273639 (C>T; OR, 0.62; 95% CI: 0.5 to 0.77; P=1.1 x 10-5) (Table 1). These SNPs reside on the same haplotype and are in high LD (CEU population LD; r2=0.94) in the PRSS1-PRSS2 locus on chromosome 7 (Figure 2). PRSS1 and PRSS2 encode for the proteases cationic and anionic trypsinogen, respective- ly. Both minor alleles rs13228878_G and rs10273639_T reduce the risk of AAP. When performing association analysis in the CEU population of 205 AAP cases and 1185 controls, rs62228256 (OR, 3.75; 95% CI: 2.27 to 6.2;
Table 1. Top 30 single nucleotide polymorphisms.
P=2.47 x 10-7), rs13228878 (OR, 0.60; 95% CI: 0.48 to 0.76; P=2.1 x 10-5) and rs10273639 (OR, 0.62; 95% CI: 0.49 to 0.78; P=3.8 x 10-5) (Online Supplementary Figures S6-8 and Online Supplementary Table S2) remained strongly associat- ed with AAP. Further investigation of previously validated SNPs within genes known to regulate trypsin activation26 (Online Supplementary Table S3) showed that AAP was associated with rs17107315 in pancreatic secretory trypsin inhibitor (SPINK1; OR, 2.87; 95% CI: 1.36 to 5.8; P=4 x 10-3), rs10436957 in chymotrypsin C (CTRC; OR, 0.69; 95% CI: 0.53 to 0.89; P=5 x 10-3) and rs4409525 in Claudin- 2 (CLDN2; OR, 1.41; 95% CI: 1.08 to 1.83; P=0.01) with all minor alleles altering AAP risk in the direction and with effects very similar to those previously reported.
In a logistic regression model, testing whether the effect of the most associated PRSS1-PRSS2 variant (rs13228878) was modified by rs17107315 (SPINK1), rs10436957 (CTRC) and rs4409525 (CLDN2), no significant interac- tions were identified (P=0.48, P=0.95 and P=0.93, respec- tively).
SNP
rs62228256
rs7270119 rs16996276 rs62228230 rs934350 rs170623 rs75245362 rs368819120 rs4769201 rs7851954 rs61734424 rs9912225 rs7155612 rs2167730 rs80170196 rs62228228 rs5010616 rs12494164 rs16848986 rs34375180 rs7139808 rs12582343 rs13228878 rs6477109 rs74109922 rs1505495 rs1791520 rs10273639 rs4655107
rs55634345
Chr Position
20 50454447
20 50436587 20 50455925 20 50445082 13 103589776
9 101984936 14 95990645 12 71747240 13 22698015 9 6796167 19 50747533 17 4680732 14 95976755 8 78103417 19 50747159 20 50443845 12 71748290
3 164967758 3 164979570 12 71779640
13 22693228 12 71766297 7 142473466 9 6794938 13 103582300
4 172973580
18 22118315
7 142456928
1 23094454
4 19846813
Major>minor MAF MAF allele cases controls
C>T 0.07 0.02
A>G 0.07 0.02
A>C 0.07 0.02
G>A 0.07 0.02
A>G 0.32 0.22
C>G 0.38 0.28
C>T 0.11 0.05
G>- 0.48 0.37
A>G 0.04 0.01
C>T 0.28 0.40
T>C 0.08 0.04
A>G 0.10 0.05
T>G 0.12 0.06
T>C 0.24 0.34
C>T 0.08 0.04
G>A 0.06 0.02
C>T 0.48 0.37
A>C 0.23 0.14
T>C 0.22 0.14
G>A 0.49 0.38
T>C 0.04 0.01
A>G 0.48 0.38
A>G 0.35 0.44
C>T 0.29 0.40
A>G 0.12 0.06
A>C 0.10 0.17
T>C 0.32 0.23
C>T 0.35 0.44
G>A 0.13 0.24
G>A 0.46 0.34
OR (95% CI)
3.75 (2.33-6.04)
3.64 (2.28-5.8)
3.64 (2.27-5.85)
3.54 (2.23-5.63)
1.84 (1.47-2.3)
1.78 (1.42-2.22)
2.46 (1.73-3.51)
1.67 (1.35-2.06)
4.66 (2.45-8.86)
0.59 (0.47-0.74)
2.75 (1.8-4.2)
2.42 (1.67-3.5)
2.24 (1.6-3.15)
0.57 (0.45-0.73)
2.73 (1.78-4.18)
3.15 (1.94-5.13)
1.63 (1.32-2)
1.77 (1.39-2.27)
1.77 (1.38-2.26)
1.61 (1.31-1.98)
4.59 (2.38-8.87)
1.62 (1.31-1.99)
0.61 (0.5-0.76)
0.61 (0.49-0.75)
2.13 (1.52-2.97)
0.48 (0.34-0.66)
1.65 (1.32-2.07)
0.62 (0.5-0.77)
0.53 (0.39-0.7)
1.58 (1.29-1.94)
P-value 5.18x10-8
5.52x10-8
8.64x10-8
9.19x10-8
1.16x10-7
3.93x10-7
6.33x10-7
2.04x10-6
2.67x10-6
3.02x10-6
3.04x10-6
3.10x10-6
3.15x10-6
3.69 x10-6
3.77x10-6
3.80x10-6
4.76x10-6
4.83x10-6
5.19x10-6
5.53x10-6
5.59x10-6
5.90x10-6
7.06x10-6
7.64x10-6
1.03x10-5
1.06x10-5
1.12x10-5
1.13x10-5
1.16x10-5
1.19x10-5
Gene (distance from gene)
ALG2 (+0.69 kb) & SEC61B (0) SCARNA13 (-9.05 kb) & SNHG10 (-8.6 kb)
KDM4C (0)
MYH14 (0)
TM4SF5 (0) & VMO1 (-7.8 kb)
MYH14 (0)
PRSS2 (-6.44 kb) & PRSS3P2 (-5.29 kb) KDM4C (0)
GALNTL6 (0)
PRSS1 (-0.4 kb) EPHB2 (0)
Top 30 SNPs most associated with AAP in 244 cases and 1320 controls.The model used here includes covariates for age and genetic ancestry. SNPs were annotated to genes if ≤10 kb upstream (-) or downstream (+) of the transcription start site or transcription terminator,respectively.SNP:single nucleotide polymorphism;Chr,:chromosome;MAF:minor allele frequency; OR: odds ratio; CI: confidence interval.
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